Optimal antimicrobial therapy of acute otitis media with effusion in early infancy is controversial. We studied the efficacy of cefaclor and amoxicillin in the treatment of 40 nonconsecutive infants less than 3 months of age in a double blind comparative trial. Infants were randomly assigned to receive either oral amoxicillin or cefaclor in a dosage of 40 mg/kg/day divided into 3 doses for 10 days. Clinical responses and adverse drug effects were evaluated at 48 to 72 hours, 5 to 7 days, 2 weeks and 3 weeks. Pathogenic bacteria isolated from ear aspirates in 24 cases included Streptococcus pneumoniae (14), Haemophilus influenzae type b (5), H. influenzae nontypeable (3), Staphylococcus aureus (4), Branhamella sp. (2), and Streptococcus pyogenes (1). Nonpathogenic bacteria isolated in 14 cases included Streptococcus epidermidis, diphtheroids and Streptococcus viridans. Two aspirates were sterile. A satisfactory clinical response was achieved in 15 of 21 cases (71%) treated with amoxicillin and 14 of 19 cases (74%) treated with cefaclor. We conclude that amoxicillin and cefaclor are comparable in efficacy for the therapy of acute otitis media with effusion in early infancy.